Thesis (Ph. D.)--Illinois State University, 1987. / Title from title page screen, viewed August 17, 2005. Dissertation Committee: Tak H. Cheung, Arlan Richardson (co-chairs), Harry Huizinga, Lynne Lucher, Mathew Nadakavukaren. Includes bibliographical references (leaves 90-102) and abstract. Also available in print.

INTRODUCTION: Diet induced obesity (DIO) is a major driving force responsible for low-grade inflammation mediated immune system decline. Impaired immune defenses lead to a number of chronic diseases and ultimately to an increased mortality. DISCUSSION: Over half a billion people worldwide are considered overweight or obese. It has been estimated that $190 billion dollars was spent in the US on obesity-related healthcare costs just in 2005. Lower productivity, lost wages, higher insurance costs, and an increased strain on the healthcare system as a whole, are the hallmarks of the obesity epidemic. Considerable body of epidemiologic evidence implicates DIO as the major cause of numerous pathologies. The obese population doesn't just suffer increased mortality from chronic conditions such as, cardiovascular disease, pulmonary diseases, Type 2 diabetes, various cancers, hyperlipidemia, hypertension, non-alcoholic fatty liver disease (NAFLD), renal failure, osteoarthritis and many other slow-onset diseases. Obese individuals also have increased mortality for more acute conditions such as N1H1 influenza virus, allergic diseases, and post-surgical complications while also lowering the efficacy for vaccinations and Helicobacter pylori eradication therapies. Today scientists recognize adipose tissue as the largest endocrine organ in the human body, releasing a myriad of paracrine and endocrine molecular factors. During DIO these adipocytokines induce a proinflammatory switch in the adipose tissue machinery, initiating chronic low-grade inflammation. Sensing an ongoing attack the immune system responds trying to maintain homeostasis. DIO however, initiates a positive feedback loop, which perpetuates inflammation and further decimates immune system's capacity to resist threats and to restore order. CONCLUSION: While the basic obesity-inflammation-disease road map has been outlined, many questions remain. Multiple areas of immunometabolism and meta inflammation require deeper understanding, but two key recommendations for future studies stand out. First, since it is easier to prevent obesity than to reverse it, attention should be focused on elucidating the endocrine role of foodstuff. Second, to find cures for chronic conditions of the ever growing obese population, scientists must elucidate the mechanism of obesity-induced inflammation's function in diminishing immune system's capacity.

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Made available in DSpace on 2014-06-11T19:33:24Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-25Bitstream added on 2014-06-13T21:06:00Z : No. of bitstreams: 1 domingues_a_dr_botfm.pdf: 3947881 bytes, checksum: 51438965cf4381a0f5691feb07f20145 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Uncaria tomentosa (Willd.) DC (Rubiaceae) is a large woody vine that is native to the Amazon and Central American rainforests and is widely used in traditional medicine for its immunomodulatory and anti-inflammatory activities. The present work used in vivo immunotoxic and in vitro immunomodulatory experiments to investigate the effects of a pentacyclic oxindole alkaloid extract from U. tomentosa bark on lymphocyte phenotype, Th1/Th2 cytokine production, cellular proliferation and cytotoxicity. For the in vivo immunotoxicity testing, BALB/c male mice were treated once a day with 125, 500 or 1250 mg/kg of U. tomentosa extract for 28 days. For the in vitro protocol, lymphocytes were cultured with 10 to 500 μL/mL of the extract for 48 h. The extract increased the cellularity of splenic white pulp and the thymic medulla and increased the number of T helper lymphocytes and B lymphocytes. Also, a large stimulatory effect on lymphocyte viability was observed. However, mitogen-induced T lymphocyte proliferation was significantly inhibited at higher concentrations of U. tomentosa extract. Furthermore, an immunological polarization toward a Th2 cytokine profile was observed. These results suggest that the U. tomentosa aqueous-ethanol extract was not immunotoxic to mice and was able to modulate distinct patterns of the immune system in a dose-dependent manner

No mundo, o nÃmero de indivÃduos cuja idade à superior a 60 anos crescerà exponencialmente e, em 2025, espera-se uma elevaÃÃo de 694 milhÃes no nÃmero de pessoas mais velhas. O envelhecimento à um processo complexo que afeta uma variedade de funÃÃes, incluindo o desenvolvimento e a manutenÃÃo do sistema imunolÃgico. Dessa forma, os idosos sÃo mais freqÃentemente acometidos por infecÃÃes e neoplasias do que os jovens. Essas patologias podem ser atribuÃdas, em parte, ao envelhecimento do sistema imunolÃgico, chamado imunossenescÃncia. O objetivo deste trabalho foi descrever o perfil imunolÃgico de uma populaÃÃo de idosos saudÃveis. Foram colhidas amostras de 35 voluntÃrios com idade igual ou superior a 60 anos, de ambos os sexos, onde foi utilizado, como controle, o mesmo nÃmero de voluntÃrios com idade entre 20 e 38 anos. Foram realizados 16 exames laboratoriais diferentes para definir as principais alteraÃÃes na imunossenescÃncia. Os resultados evidenciaram alteraÃÃes tanto na imunidade inata, quanto na imunidade adaptativa no organismo idoso. As alteraÃÃes encontradas na imunidade inata foram: aumento do nÃmero de neutrÃfilos no sangue venoso; aumento da concentraÃÃo do componente C4 do complemento; e aumento da concentraÃÃo de interleucina-6. As alteraÃÃes da imunidade adaptativa foram: reduÃÃo na quantidade dos linfÃcitos (leucograma) e das subpopulaÃÃes linfocitÃrias CD2+, CD3+ e CD8+ (imunofenotipagem); e aumento na concentraÃÃo da imunoglobulina IgA e diminuiÃÃo da concentraÃÃo de IgM. Podemos concluir, dessa forma, que este trabalho foi de grande relevÃncia para definir os parÃmetros normais do sistema imunolÃgico de um indivÃduo idoso saudÃvel e aperfeiÃoar a nossa compreensÃo deste sistema. Assim, tambÃm se constitui num passo necessÃrio no sentido de identificar, no futuro, formas de melhor tratar as causas subjacentes da imunossenescÃncia e suas conseqÃÃncias. / Worldwide, the number of individuals whose age is over 60 years will grow exponentially. Is provided an increase of 694 million in the number of older people in 2025. Ageing is a complex process that negatively impacts the development of the immune system and its ability to function. Immunosenescence is a multifactorial condition leading to many pathologically significant health problems in the aged population, it is becoming recognized that the immune system declines with age, a term known as immunosenescence, which leads to a higher incidence of infections, neoplasia and autoimmune diseases. This study attempts to describe the immunological profile of a population of healthy elderly. Thirty five elderly patients aged 60 years were subjected to a study and the same numbers of young volunteers aged between twenty and thirty eight were examinated like control group. Were investigated sixteen laboratorial exams to define the main changes in immunosenescence. The results showed changes in both innate immunity and adaptive immunity in the elderly body. The changes found in innate immunity were: increase the number of neutrophils in venous blood, increasing the concentration of C4 complement component, and increased levels of interleukin-6. Changes in adaptative immunity were: reduction in the number of lymphocytes (WBC) and lymphocyte subsets CD2 +, CD3 + and CD8 + (immunophenotyping) and increased concentration of immunoglobulin IgA and decreased IgM concentration. In cloncusion, this work was important to define the normal parameters of the immune system of a healthy elderly and improve our understanding of this system. Thus, it also constitutes a necessary step to identify how best to treat the underlying causes of immunosenescence and its consequence.

University of Macau / Institute of Chinese Medical Sciences

Surgical resection is the leading treatment of most solid tumours, however surgical stress creates an immunosuppressive environment that promotes metastases. A global decrease in T cell numbers and function post-surgery has been documented. However, the effect on tumour associated antigen (TAA)-specific T cells remains unclear. The objective is therefore to evaluate the impact of surgical stress on TAA-specific adaptive T cell immunity. Melanoma tumour-bearing C57BL/6 mice were vaccinated using AdhDCT, an adenovirus expressing dopochrome totaumerase (DCT), a melanoma TAA, and underwent abdominal nephrectomies to induce surgical stress. Surgical stress decreased the number of splenic cytotoxic T cells (CTLs) and their capacity to produce immunostimulatory cytokines (IFNγ and TNFα), as determined by flow cytometry. A perioperative accumulation in CTL-suppressive MDSCs was observed and demonstrated a direct suppression of CTL IFNγ and TNFα production and secretion. Understanding the mechanisms of perioperative T cell dysfunction will facilitate the development of targeted immunotherapies.

Background: Cancer is a crippling disease affecting 32.6 million people globally. It is currently ranked as the leading cause of death worldwide, and is associated with significant morbidity and mortality. Despite advances made in the prevention, detection and treatment of malignancy, there remains a dearth of accurate and feasible prognostic and predictive factors for use in the management of patients suffering from cancer in developing countries. It is widely recognized that the immune system plays a fundamental role in regulating the development and progression of malignancy. T-lymphocytes in particular have been categorized into T-cell populations which either promote (T regulatory cells) or prevent (CD4+ and CD8+ T-lymphocyte) cancer development and progression. Aim: The aim of this thesis was to evaluate whether the levels of the respective pro- (T regulatory) and anti- (CD4+ and CD8+ T-lymphocytes) cancer T-lymphocyte subsets before treatment, and alterations of these levels following conventional anticancer treatment (surgery, chemotherapy and radiotherapy) could be used as markers of prognosis in conjunction with other well known prognostic factors, or as predictors of short term (5-7 weeks post-treatment) survival. Methods: Blood samples were collected from 25 breast cancer, and 10 oesophageal cancer patients before antitumor treatment, at day 1 post-treatment and at 5-7 weeks post-treatment. The circulating concentrations and percentages of CD4+, CD8+ and T regulatory cells were determined from whole blood by flow cytometry. These levels were used to determine the CD4: CD8+ T-cell ratio, the CD4+ Treg: total CD4+ Treg ratio and the CD8+ Treg: total CD8+ Treg ratio. Results: Early (stage 1 and 2) HER-2/neu negative breast cancer was associated with a higher CD4+ (558 versus 133 cells/μl; P=0.05) and CD8+ T-cell count (198 versus 58 cells/μl; P=0.05) as compared to early HER-2/neu positive breast cancer. Breast cancer patients showed a significant decline in CD8+CD25+CD127+ Treg cell subsets (P=0.012) following antitumor treatment. However, oesophageal cancer patients showed an increasing trend in CD8+CD127+FoxP3+ Treg cells at day 1 post-treatment (P=0.045) and at 5-7 weeks posttreatment (P=0.044). Patients who demised displayed a significantly lower CD4+: CD8+ Tcell ratio (1.2 versus 2.2; P=0.044) before treatment, as well as a lower CD4+ (111 versus 390 cells/μl; P=0.0046) and CD8+ T-cell count (88 versus 160 cells/μl; P=0.058) at day 1 posttreatment, as compared to those who survived. While patients who survived displayed a higher CD8+ Treg: total CD8+ T-cell ratio (1.48 versus 0.53 P=0.0126) before treatment, and a higher CD4+CD25+CD127+ Treg cell level at day 1 post-treatment (9 versus 2 cells/μl; P=0.047), as compared to those who demised. Conclusion Taken together the findings of this thesis suggest that the CD4+ and CD8+ T-cell count and CD4:CD8 T-cell ratio may serve as predictors of short-term survival in the management of breast and oesophageal cancer. Furthermore, HER-2/neu receptor status may reflect the underlying immune status and antitumor effector activity of a patient. These findings also suggest that T regulatory cell subsets are a heterogeneous group of cells with variable frequencies at presentation and in responses to antitumor treatment depending on the cancer type, stage of disease and antitumor treatment employed. This further illustrates the need for more work aimed at better characterizing the different Treg cell subsets to better identify which subsets are associated with patient prognosis. In summary, this work presents evidence to suggest a role for the T-cell immune profile as a prognostic and predictive parameter in the management of cancer. It argues for early assessments of cancer patients’ immune status as part of the diagnostic work up and that the immune status is taken into consideration when decisions are made regarding treatment. / Dissertation (MSc)--University of Pretoria, 2014. / tm2015 / Immunology / MSc / Unrestricted

Objectives: The effects of estrogens on immune system formation and function are well documented. Diethylstilbestrol (DES), a synthetic estrogen, has been linked to neoplasia and immune cell dysfunction in humans and animals exposed in-utero. In-vitro effects of DES exposure of murine embryonic stem (ES) cells on the early embryonic immune system development and the expression of cellular surface markers associated with common hemangioblastic and hematopoietic precursors of the endothelial, lymphoid & myeloid lineages were investigated. Hypothesis: Early ES cell expression of CD45 a marker common to lymphoid lineage hematopoietic stem cells and differentiation of lymphoid lineage precursors are affected by in-vitro exposure to DES. Methods: Murine ES cells were cultured using a variety of techniques: an OP9 co-culture system, and formation of embryoid bodies (EBs) in a liquid medium and hanging drop system. The OP9 co-culture system did not appear to give rise to well differentiated lymphoid lineage cells during 12 days of differentiation. The hanging drop EB culture system, previously shown to promote differentiation of endothelial and lymphoid precursor cells, was chosen for further studies of ES cell differentiation. ES cells were harvested at five time points: undifferentiated (day 0), and differentiated (days 3, 8, 12 and 16). Differentiating ES cells were treated with DES beginning on day 3. The synthetic estrogen, DES, was chosen as a treatment because of its similar potency to 17β estradiol and documented association with neoplasia in women exposed in-utero. Surface marker expression, measured by real-time RT-PCR amplification, was recorded using fluorogenic TaqMan(R) probes designed specifically for the surface proteins of interest: oct4, c-Kit, Flk1, ERα, ERβ, CD45, Flt1, & VE-cadherin. Analysis & Results: Changes in surface marker gene expression between day 0 and day 16 of differentiation were analyzed using the RT-PCR threshold counts (CT) and the comparative threshhold cycle method. The expression of each target mRNA was normalized internally to a housekeeping gene (18s rRNA) and calculated relative to day 0. ANOVA (Type 3 fixed-effects analysis, SAS) was performed using the unexponentiated ΔΔCT values. The effects of DES, time, and the interaction between DES and time were evaluated for days 8, 12 and 16. Additionally, the effects of DES on the expression of each marker were evaluated for day 16. Expression of estrogen receptor receptor α & β (ERα & β) in the EBs was established, and did not appear to be affected at any time by treatment with DES. ERα was expressed in significant levels on day 16, while ERβ was expressed in low levels throughout the period of differentiation. The expression of the cell surface marker, c-Kit was significantly (P<0.0001) altered by the presence of DES between the three time points sampled. The expression of the VEGF receptor, Flt1, and the adhesion molecule, VE-cadherin, markers of endothelial cells, were also significantly (P<0.026) altered by treatment with DES on day 16 of differentiation. Treatment with DES appeared to have no effect on the expression of CD45, a marker common to lymphoid precursor cells. Conclusions: These results indicate the presence of estrogen receptors in differentiating ES cells as early as day three in-vitro (ERβ) until day 16 (ERα). DES alters expression of common hemangioblastic and hematopoietic precursor, as well as endothelial lineage markers, but has no effect on expression of the marker of lymphoid lineage development before day 16. These effects coincided with the expression of ERα. The enduring effects of DES exposure in-utero may not be manifest in this ES model, or may occur at later stages of differentiation or in selected subpopulations of CD45+ cells. / Master of Science

Knowledge of human T cell responses and the pathways for their differentiation and maintenance from development into adulthood remains largely sparse. Much of what is known concerning the adaptive immune response in humans derives from analysis of peripheral blood, even though the majority of T cells within the body reside in tissue sites. We have established a protocol with LiveOnNY, the organ procurement organization of the New York metropolitan area allowing us access to healthy tissues from individual organ donors of a diverse background. Through novel analysis of lymphoid and mucosal tissues from infant and adult organ donors, we reveal how naïve, regulatory, and memory T cells dynamically populate and are maintained in tissues and circulation over the human lifespan. An initial multidimensional, quantitative analysis of human T cell compartmentalization involving 56 organ donors of a broad age range revealed that distribution of naïve, effector, and memory T cell subsets is largely dependent on tissue localization and differentiation state. Furthermore, T cell homeostasis driven by cytokine or TCR-mediated signals is dependent on CD4+or CD8+ T cell subset. Examining whether T cell subset distribution was set at birth, we compared T cell populations from a cohort of pediatric organ donors in the first two years of life to tissues from young adult donors aged 15-25 years. Results show a dynamic compartmentalization of naïve and regulatory T cells in all tissues early in life that is rapidly replaced with effector memory T cells (TEM) especially in mucosal sites further revealing the importance of a local adaptive immune response. Interestingly, the proportion and distribution of these T cell populations in tissue sites show varying levels of reliance on thymic output. Further evidence for the compartmentalization of the adaptive immune response and mechanisms for T cell maintenance throughout life can be shown through the analysis of T cell receptor sequences. We examined naïve and TEM populations in lymph nodes and spleen as a function of thymic output revealing low sharing of the naïve T cell repertoire between tissue sites with higher amounts of overlapping clones seen in TEM populations, especially with CD8+ T cells. These differences highlight potentially different roles for CD4+ and CD8+ T cells in the response to pathogen and their maintenance with age.